60 kda in a cell will con tain a single bound

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~ 60 kDa) in a cell will con- tain a single bound platinum atom, whereas hundreds or thousands of Pt atoms are coordinated to DNA (M.W. ~ 1011). If the replication apparatus cannot bypass these lesions, then cell division will not occur, and tumor growth is inhibited.
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534 9 / METALS IN MEDICINE Although these and other results all point to DNA as an important cellular target of cisplatin, most likely responsible for its anticancer activity, this infor- mation does not explain why tumor cells are more affected by cis-DDP than non-tumor cells of the same tissue. Moreover, why is trans-DDP, which also enters cells, binds DNA, and inhibits replication, albeit at much higher doses (see discussion below), not an active anticancer drug? What causes cisplatin to kill cells and not merely to arrest tumor growth? The latter can be explained by DNA synthesis inhibition, but not necessarily the former. Very recent studies have begun to address these questions using powerful new methodologies of molecular and cell biology, as described in subsequent sections of this chapter. The results, although preliminary, continue to point to DNA as the most impor- tant cellular target of cisplatin. 3. Aspects of platinum binding to DNA Given that DNA is a major target of platinum binding in cells, it is incum- bent upon the bioinorganic chemist to investigate the nature of these interactions and their biological consequences. Of all the ligands studied in coordination chemistry, DNA is surely among the most complex. In the ensuing discussion, we first present experiments that delineate the chemical steps involved in cis- and trans-DDP binding to DNA as well as the chemical consequences of the adducts formed. We next describe the physical changes in the double helix that accompany platinum binding, and then we discuss the biological consequences that attend the platination of DNA. Subsequent sections describe the major ad- ducts formed, in other words the regiospecificity of the drug, the three-dimen- sional structures of the adducts, and the way in which different structures within DNA can modulate platinum binding. Finally, we consider the response of the cell to Pt-DNA adducts, including studies with site-specifically modified DNA, and speculate about how this chemistry might relate to the antitumor drug mech- anism. a. Kinetics of Platinum Binding to DNA The binding of cis- and trans- DDP to DNA has been studied 67 by 195pt NMR spectroscopy with the use of isotopically enriched 195Pt, which has a nuclear spin I = !. The DNA used in this experiment was obtained from chicken red blood cell chromosomes that had been enzymatically degraded to relatively small pieces ranging from 20 to 60 base pairs in length (molecular-weight range 13 to 30 kDa). Since the 195Pt chemical shifts are very sensitive to chemical environment, this NMR study provided important details about the kinetics and mechanism of platinum bind- ing to the biopolymer. The rate-determining step in platination of the DNA is loss of chloride ion (Equation 9.5) to form the monoaqua complex, which rap- idly coordinates to a nitrogen donor on the nucleic acid. The identification
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